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EP2167128A2 - Anticorps hybrides modifiés dirigés contre l'intégrine alpha v - Google Patents

Anticorps hybrides modifiés dirigés contre l'intégrine alpha v

Info

Publication number
EP2167128A2
EP2167128A2 EP08784834A EP08784834A EP2167128A2 EP 2167128 A2 EP2167128 A2 EP 2167128A2 EP 08784834 A EP08784834 A EP 08784834A EP 08784834 A EP08784834 A EP 08784834A EP 2167128 A2 EP2167128 A2 EP 2167128A2
Authority
EP
European Patent Office
Prior art keywords
antibody
seq
tumor
heavy chain
engineered
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP08784834A
Other languages
German (de)
English (en)
Other versions
EP2167128B1 (fr
Inventor
Simon Goodman
Diane Hahn
Francesc Mitjans
Jaume Adan
Kin-Ming Lo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Priority to PL08784834T priority Critical patent/PL2167128T3/pl
Priority to EP12004296A priority patent/EP2526967A1/fr
Priority to SI200830845T priority patent/SI2167128T1/sl
Priority to EP08784834A priority patent/EP2167128B1/fr
Publication of EP2167128A2 publication Critical patent/EP2167128A2/fr
Application granted granted Critical
Publication of EP2167128B1 publication Critical patent/EP2167128B1/fr
Priority to CY20121101248T priority patent/CY1113493T1/el
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2842—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta1-subunit-containing molecules, e.g. CD29, CD49
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567—Framework region [FR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/72—Increased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • BACKGROUND OF THE INVENTION Treatment of cancer remains a major problem in health care.
  • One proposed strategy for treatment of cancer is inhibition of angiogenesis and thus inhibiting the generation and development of blood vessels, which supply the tumor with growth relevant means.
  • a second strategy is direct inhibition of specific receptors on tumor cell surfaces, such as the inhibition of Her2 by Herceptin® or inhibition of EGFR by cetuximab (Erbitux®).
  • Inhibitors of integrins are considered to be potentially useful anti-tumor agents, because integrins are expressed on tumor neovasculature and mediate angiogenesis.
  • integrins are expressed on certain tumor cells and may directly promote tumor growth and survival.
  • a first anti-integrin drug is cilengitide and is considered to be a useful antitumor agent (Eskens FA, et al. (2003) Eur J Cancer 39:917-26).
  • cilengitide is a small molecule that must be dosed frequently.
  • the structure of cilengitide, selected salt form e.g. are disclosed in EP0770622, WO 0015244 and PCT/us07/01446 and are disclosed herein by reference.
  • Mouse mAb 17E6 is produced by hybridoma cell line 272-17E6 and deposited under accession number DSM ACC2160. Mouse 17E6 antagonizes integrin interaction with the extracellular matrix (ECM), and perturbs the function of endothelial and tumor cells. Primary effects of the antibody include disrupting endothelial cell (EC) adhesion and movement, inducing their apoptosis, and suppressing the activation of growth factor pathways.
  • ECM extracellular matrix
  • Blockade by said antibody directly suppresses survival of both the activated endothelial cells and some tumor cells.
  • Monoclonal antibodies such as 17E6 are generally useful for the inhibition of extracellular protein-protein interactions, such as the inhibition of ligand-receptor interactions.
  • monoclonal antibodies are often difficult to express and often provoke an immune response, such as an anti-idiotypic response, which limits their effectiveness.
  • Such an engineered antibody should have the potential to suppress the development of the tumor both indirectly, via the tumor vasculature, and directly on the tumor cells themselves.
  • the invention relates to new antibodies having the biological characteristics of monoclonal mouse antibody 17E6 (EMD 73034) but wit improved properties above all with respect to immunogenicity in humans and satisfying expression in mammalian expression systems in an industrial production and manufacturing scale.
  • the invention provides a few engineered antibodies having modified sequences, which recognize the same receptor epitope as mouse antibody 17E6 but show reduced immunogenicity in humans and can be better expressed as the comparable non-modified antibody.
  • modifying or engineering a mouse derived antibody in order to obtain reduced immunogenicity in humans is, as a rule, accompanied by a distinct loss of expression and / or binding affinity.
  • chimerization or humanization according to well known standard techniques usually leads to a decrease of expression, binding affinity etc., which can only partially resolved by specific back mutations or other measures. Modifications within a respective protein molecule that are simultaneously successful with respect to reduced immunogenicity, high expression and satisfying binding affinity cannot be predicted.
  • decreasing the number of T-cell epitopes in order to eliminate or reduce an immune response against the drug in a human as primary problem to be solved may lead to non-tolerable loss of expression or binding affinity or both that would lead to further problems to be solved.
  • Humanized monoclonal antibody 425 (matuzumab) is known, for example from EP 531 472, and derives from its murine counterpart 425 ( mouse MAb 425, ATCC HB9629), The antibody was raised against the human A431 carcinoma cell line and found to bind to a polypeptide epitope on the external domain of the human epidermal growth factor receptor (EGFR). It was found to inhibit the binding of epidermal growth factor (EGF) at both low and high affinity EGFR sites.
  • Matuzumab has shown in clinical trials high efficacy.
  • the FR sequences of the light chain of matuzumab are depicted in SEQ ID Nos. 12 - 15 as specified below and in the claims.
  • FRs modified heavy chain framework regions from anti-integrin mouse antibody 17E6 with light chain frame work regions of a differently specific humanized anti-EGFR antibody h425 (matuzumab) has generated - apart from other modification - some antibodies with superior immunogenic properties, which are furthermore sufficiently expressed in standard mammalian expression systems.
  • VL region (FRs) from mAb h425 surprisingly the expression level is distinctly increased, but, as shown later, further mutations had to be done in order to improve other properties, above all, binding affinity.
  • a further important modification is the replacement of an amino acid residue within the CDR2 region of the heavy chain of mouse 17E6.
  • protein stability and expression level can be distinctly improved at least compared to a chimeric 17E6 version.
  • Further improvements in expression and stability can be obtained by replacing the original mouse IgGI heavy chain constant region by a human lgG2 with a modified human IgGI hinge region.
  • said lgG2 can be further modified by replacing an ariginine residue at position 297 by an glutamine (N297Q). This modification eliminates an N- glycosylation site and thus abolishes or reduces ADCC and CDC activity of the antibodies to be engineered.
  • N297Q glutamine
  • the corresponding DNA sequences of DI-17E6 are shown in Figures 17 - 19.
  • the invention is also directed to engineered antibodies as described above and below which are fused directly or via a linker molecule to cytokines, such as IL-2, IL-12, TNFa, IFNa, IFNb 1 or growth factors.
  • cytokines such as IL-2, IL-12, TNFa, IFNa, IFNb 1 or growth factors.
  • Antibody fusion cytokines may be also used in tumor therapy and / or angiogenesis related diseases because the cytokine portion may contribute to an increased cytotoxicity.
  • Antibody fusion proteins, especially immunocytokines are well known in the art.
  • a preferred fusion protein according to the invention is DI-17E6-IL2, or DI-17E6-(L)-.IL2, wherein L is a linker peptide.
  • the engineered antibodies as described can be used in pharmaceutical compositions for the treatment of angiogenesis related diseases and / or tumor related disease.
  • the antibodies according to the invention elicit a direct effect on tumor growth which seems to be independent on the indirect anti-tumor effect caused by blocking angiogenesis.
  • the combination of the preferred engineered antibody DI-17E6 or similar variants with anti-EGFR antibodies, preferably cetuximab causes a surprising effect, namely the delay or prevention of re-growth of tumor tissue after stopping administration with the engineered antibody, preferably DI-17E6.
  • the pharmaceutical composition comprising a second therapeutic agent may be also used as a kit of parts comprising in a first package the the engineered antibody, preferably DI-17E6, and in a second package a second therapeutic agent, for example, an angiogenesis inhibitor, a chemotherapeutic agent or a tyrosine kinase inhibitor, such as an anti-EGFR or anti-Her2 antibody .
  • a second therapeutic agent of said kit is the angiogenesis inhibitor cilengitide or the anti-EGFR antibody cetuximab or matuzumab or a chemotherapeutic agent.
  • An engineered recombinant anti- ⁇ v-integrin hybrid antibody comprising (i) a CDR light and a heavy chain region deriving from mouse monoclonal anti- ⁇ v integrin antibody 17E6 (ii) a light chain framework region which is taken from humanized monoclonal anti-EGFR antibody 425, (iii) a heavy chain framework region deriving from mouse monoclonal anti- ⁇ v integrin antibody 17E6, and
  • CDR1 RASQDISNYLA (SEQ ID NO. 5)
  • CDR2 YTSKIHS (SEQ ID No. 6);
  • CDR3 QQGNTFPYT (SEQ ID No. 7), and the CDR heavy chain regions are:
  • CDR1 RASQDISNYLA (SEQ ID NO. 5);
  • CDR2 YINPRSGYTEYNEIFRD (SEQ ID NO. 9), and
  • FR3 KATMTADTSSSTAYMQLSGLTSEDSAVYYCAS (SEQ ID NO. 18)
  • FR4 WGQGTSVTVSS (SEQ ID NO. 19), wherein one, more or all of the bold and underlined positions are mutated in order to reduce or eliminate T-cell epitopes and thus immunogenicity in a human , and
  • EMD 525797 One of the features of EMD 525797 is not to trigger immune responses.
  • the constant regions of the immunoglobulin were also modified as follows.
  • the genomic human kappa constant region was used.
  • the genomic human gamma-2 (72) constant regions were used, but the hinge region with the four cysteine disulfide bonds was replaced by a modified y1 hinge region to minimize disulphide bond scrambling and to improve expression.
  • a mutation of Asn-297 in the CH2 domain to GIn (N297Q) was introduced to remove the N-glycosylation signal: the resultant de-glycosylation abrogates effector functions and prolongs serum half-life of the antibody.
  • DI-17E6 uses a combination of mechanochemical and biochemical effects to affect endothelia and to increase stress on tumor cells.
  • FIG 12 In vivo -effect of DI-17E6 (EMD 525797) in combined treatment with darcabazine (DTIC) xenografts tumor models using human MeWo tumor cells transplanted into mice using suboptimal doses of DI-17E6.
  • EMD 525797 started at the same day than tumor cell injection.
  • Treatment of DTIC started at day 11 after tumor cell injection.
  • EMD 525797 was administered once per week i.p. at 500 ⁇ g/dose.
  • DTIC was administered once per week i.p. at 50 mg/Kg.
  • the pdHLlO-DI-17E6(C60Y)y2h(N297Q) vector contains G at 80J, Tat 985, C at 993, Tat lOO ⁇ , T at 1045 and A at 1071.
  • the published sequence contains C, A, A, G, AC (an additional nt), and G at these respective positions.
  • DI-17E6 inhibited growth of M21-L tumors in the SCID mouse-human skin chimera model and was active at a dose of 1 mg/dose administered i.p. 3 times per week starting treatment one day after tumor ceil inocuiation (Figure 4),. This finding demonstrates that EMD 525797 elicits an anti-angiogenic effect on tumor growth.
  • Treatment dosings for EMD 525797 were adjusted to the expected serum trough values of 100 ⁇ g/ml. To reach this serum trough values, animals were dosed following a single loading dose of 17.1 mg/kg plus multiple (weekly) maintenance dose of 5.1 mg/kg scheduling as described in the next table.

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  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
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  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Oncology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

L'invention concerne des anticorps modifiés qui se lient spécifiquement à des récepteurs d'intégrine, en particulier à la sous-unité alpha V du récepteur de l'intégrine. Les anticorps précités comprennent les sites de liaison à l'antigène (CDR) d'un anticorps anti-intégrine murin connu, et des séquences variables de la chaîne légère hybrides, des séquences variables de la chaîne lourde mutées (Fr) et des séquences constantes de la chaîne lourde modifiées. Les anticorps de l'invention possèdent des propriétés d'expression et des propriétés immunogènes améliorées et suscitent une excellente activité anti-angiogénique et anti-tumorale chez les humains en monothérapie, mais également et par-dessus tout, lorsqu'ils sont combinés à d'autres agents inhibiteurs de l'angiogenèse et des tumeurs.
EP08784834A 2007-07-17 2008-07-17 Anticorps hybrides modifiés dirigés contre l'intégrine alpha v Active EP2167128B1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PL08784834T PL2167128T3 (pl) 2007-07-17 2008-07-17 Skonstruowane metodami inżynierii hybrydowe przeciwciała skierowane przeciwko integrynie alfa-v
EP12004296A EP2526967A1 (fr) 2007-07-17 2008-07-17 Anticorps hybrides à intégrine v anti-alpha modifiées
SI200830845T SI2167128T1 (sl) 2007-07-17 2008-07-17 Z genetskim inĺ˝enirstvom pridobljena hibridna protitelesa proti alfa v- integrinu
EP08784834A EP2167128B1 (fr) 2007-07-17 2008-07-17 Anticorps hybrides modifiés dirigés contre l'intégrine alpha v
CY20121101248T CY1113493T1 (el) 2007-07-17 2012-12-21 Τροποποιημενα υβριδικα αντισωματα αντι-αλφα v- ιντεγκρινης

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP07013964 2007-07-17
PCT/EP2008/005852 WO2009010290A2 (fr) 2007-07-17 2008-07-17 Anticorps hybrides modifiés dirigés contre l'intégrine alpha v
EP08784834A EP2167128B1 (fr) 2007-07-17 2008-07-17 Anticorps hybrides modifiés dirigés contre l'intégrine alpha v

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP12004296A Division-Into EP2526967A1 (fr) 2007-07-17 2008-07-17 Anticorps hybrides à intégrine v anti-alpha modifiées

Publications (2)

Publication Number Publication Date
EP2167128A2 true EP2167128A2 (fr) 2010-03-31
EP2167128B1 EP2167128B1 (fr) 2012-10-24

Family

ID=40029330

Family Applications (2)

Application Number Title Priority Date Filing Date
EP12004296A Withdrawn EP2526967A1 (fr) 2007-07-17 2008-07-17 Anticorps hybrides à intégrine v anti-alpha modifiées
EP08784834A Active EP2167128B1 (fr) 2007-07-17 2008-07-17 Anticorps hybrides modifiés dirigés contre l'intégrine alpha v

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP12004296A Withdrawn EP2526967A1 (fr) 2007-07-17 2008-07-17 Anticorps hybrides à intégrine v anti-alpha modifiées

Country Status (19)

Country Link
US (1) US8562986B2 (fr)
EP (2) EP2526967A1 (fr)
JP (1) JP5341889B2 (fr)
KR (1) KR101559596B1 (fr)
CN (1) CN101687039B (fr)
AU (1) AU2008277907B2 (fr)
BR (1) BRPI0815567B8 (fr)
CA (1) CA2693863C (fr)
CY (1) CY1113493T1 (fr)
DK (1) DK2167128T3 (fr)
EA (1) EA019485B1 (fr)
ES (1) ES2395799T3 (fr)
HR (1) HRP20120949T1 (fr)
IL (1) IL203269A (fr)
PL (1) PL2167128T3 (fr)
PT (1) PT2167128E (fr)
SI (1) SI2167128T1 (fr)
WO (1) WO2009010290A2 (fr)
ZA (1) ZA201001124B (fr)

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PL2672994T3 (pl) 2011-02-11 2018-11-30 Merck Patent Gmbh Przeciwciało przeciwko integrynie alfa-v do leczenia raka prostaty
WO2015035215A1 (fr) * 2013-09-05 2015-03-12 Amgen Inc. Molécules contenant des fc et présentant des profils de glycoforme prévisibles, uniformes et reproductibles
ES2897782T3 (es) 2014-09-17 2022-03-02 Merck Patent Gmbh Método de tratamiento de las enfermedades de la metástasis ósea, medicamentos para el tratamiento y método para predecir el resultado clínico del tratamiento de las enfermedades causadas por metástasis ósea
ES2856348T3 (es) 2014-09-17 2021-09-27 Merck Patent Gmbh Un método para el tratamiento de cánceres sólidos y/o metástasis de los mismos, medicamentos relacionados, y un método para la predicción de la evolución clínica del tratamiento de cánceres sólidos y/o metástasis de los mismos
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JP7123063B2 (ja) 2017-02-02 2022-08-22 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング 抗体ドメインの好ましい対形成
CN108948206B (zh) * 2017-05-23 2022-08-23 赵磊 一种抗egfr/pd-1双靶向抗体、其制备方法及用途
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CN115666704B (zh) 2019-12-13 2025-09-26 比特比德科有限责任公司 用于将治疗剂递送至胃肠道的可摄取装置
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JP2010533480A (ja) 2010-10-28
KR20100057010A (ko) 2010-05-28
AU2008277907B2 (en) 2013-08-22
SI2167128T1 (sl) 2013-01-31
CA2693863C (fr) 2017-10-03
EA019485B1 (ru) 2014-04-30
BRPI0815567B1 (pt) 2019-06-04
BRPI0815567B8 (pt) 2021-05-25
IL203269A (en) 2014-11-30
KR101559596B1 (ko) 2015-10-12
ES2395799T3 (es) 2013-02-15
US8562986B2 (en) 2013-10-22
PT2167128E (pt) 2013-01-24
ZA201001124B (en) 2010-11-24
CY1113493T1 (el) 2016-06-22
EP2526967A1 (fr) 2012-11-28
EP2167128B1 (fr) 2012-10-24
PL2167128T3 (pl) 2013-03-29
AU2008277907A1 (en) 2009-01-22
CN101687039A (zh) 2010-03-31
WO2009010290A3 (fr) 2009-04-09
DK2167128T3 (da) 2012-12-03
WO2009010290A2 (fr) 2009-01-22
HK1143523A1 (en) 2011-01-07
BRPI0815567A2 (pt) 2015-02-18
HRP20120949T1 (en) 2012-12-31
JP5341889B2 (ja) 2013-11-13
EA201070150A1 (ru) 2010-08-30
US20100254977A1 (en) 2010-10-07
CA2693863A1 (fr) 2009-01-22
CN101687039B (zh) 2014-04-16

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